JACC: Heart Failure Vol. 1, No. 3, 2013� 2013 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.03.005

Left Bundle Branch Block Predicts BetterSurvival in Women Than Men ReceivingCardiac Resynchronization Therapy

Long-Term Follow-Up of w145,000 Patients

Zak Loring, BS,*y Daniel A. Caños, MPH,* Kimberly Selzman, MD, MPH,*z Naomi D. Herz, BS,*

Henry Silverman, BS,x Thomas E. MaCurdy, PHD,x Christopher M. Worrall, BS,kJeffrey Kelman, MD, MMSC,k Mary E. Ritchey, PHD,* Ileana L. Piña, MD, MPH,*{David G. Strauss, MD, PHD*

Silver Spring, Maryland; Durham, North Carolina; Salt Lake City, Utah; Burlingame, California;Baltimore, Maryland; and Bronx, New York

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lingame, California; kCenland; and the {Division

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he goal of this study was to test the hypothesis that in recipients of cardiac resynchronization therapy defibrillators(CRT-D), conventional left bundle branch block (LBBB) diagnosis predicts better survival in women than in men.

Background N

ewYorkHeart Association class I and II patientswithout LBBBdo not benefit fromCRT-D, andwomenhave better survivalafter CRT-D thanmen. Separate analysis suggests that QRS duration thresholds for LBBB diagnosis differ according to sex,and conventional LBBB electrocardiographic criteria are falsely positive in men more frequently than in women.

Methods W

e analyzedMedicare records from144,642CRT-D recipients between2002and2008 thatwere followedup for up to90 months. Medicare billing data were used to determine age, sex, race, and comorbidities. Hazard ratios (HRs) werecalculated to assess if conventional LBBB diagnosis had different prognostic significance according to sex.

Results In

univariate analysis, LBBB was associated with a 31% reduction in death in women (HR: 0.69 [95% confidenceinterval (CI): 0.67 to 0.71]) but only a 16% reduction in death in men (HR: 0.84 [95% CI: 0.82 to 0.85]). Inmultivariable analyses controlling for comorbidities, LBBB was associated with a 26% reduction in death in women(HR: 0.74 [95% CI: 0.71 to 0.77]) and a 15% reduction in death in men (HR: 0.85 [95% CI: 0.83 to 0.87]). Asignificant interaction (p < 0.0001) between sex and LBBB was seen.

Conclusions L

BBB diagnosis is associated with greater survival in women than in men receiving CRT-D, and this discrepancy is notexplainedbydifferences inmeasuredcomorbidities.Possibleexplanations for thisdifference include thatLBBBmayhavedifferent prognostic significance according to sex or that LBBB diagnosis is more often false-positive in men comparedwith women. (J Am Coll Cardiol HF 2013;1:237–44)ª 2013 by the American College of Cardiology Foundation

Cardiac resynchronization therapy defibrillators (CRT-D)reduce mortality and heart failure (HF) hospitalizations inpatients with reduced left ventricular (LV) ejection fractionand prolonged QRS duration (QRSD) (1–5). However,recent analysis of clinical trials enrolling New York Heart

Radiological Health, US Food and Drug

land; yDuke University School of Medicine,

f Cardiology, Department of Internal Medicine,

cine, Salt Lake City, Utah; xAcumen, LLC,

ters for Medicare & Medicaid Services, Balti-

of Cardiology, Albert Einstein College of

ject was supported by the Centers for Medicare

rug Administration (FDA) SafeRx Project and

. All authors have reported that they have no

of this paper to disclose.

, 2012; revised manuscript received March 4,

Association class I and II patients found that clinicalbenefit was greatest in (and in some cases limited to) patientswith left bundle branch block (LBBB) (6–8). In addition,analysis of Medicare patients receiving CRT-D in theAmerican College of Cardiology Implantable Cardioverter-Defibrillator Registry demonstrated that LBBB was astrong predictor of both freedom from HF hospitalizationand overall survival (9). These findings have promptedinterest in developing a better understanding of how to bothdiagnose LBBB and integrate it into current indications forcardiac resynchronization therapy (CRT) (10,11).

Previous studies have demonstrated that women have betterlong-term survival after CRT than men (12,13). However,subgroup analysis of CRT-D trials to investigate the source ofthis sex disparity has been limited because women representedonly 24% of enrolled patients (14). This underrepresentation

Abbreviationsand Acronyms

CI = confidence interval

CRT = cardiac

resynchronization therapy

CRT-D = cardiac

resynchronization therapy

defibrillators

HF = heart failure

HR = hazard ratio

ICD-9-CM = International

Classification of Diseases-

Ninth Revision-Clinical

Modification

LBBB = left bundle branch

block

LV = left ventricular

RBBB = right bundle branch

block

QRSD = QRS duration

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may cause sex differences in theprognostic value of clinical vari-ables to be overshadowed. Arecent meta-analysis found thatclinical benefit from CRT-Dwas limited to patients withQRSD �150 ms (14); however,this finding did not take intoaccount QRS morphology, andQRSD �150 ms may thus be anindirect marker of LBBB, whichhas been shown to be a betterpredictor of CRT outcomes thanQRSD (11,15). Recent studieshave suggested that women withLBBB have shorter QRSD thanmen because women have smallerventricles and shorter QRSD inthe absence of LBBB (10,16).Thus, limiting CRT-D to pa-tients with QRSD �150 ms may

deny CRT-D to women with complete LBBB who are likelyto benefit from this device.

Endocardial mapping studies have found that one-thirdof patients diagnosed with LBBB by using conventionalelectrocardiographic criteria do not have endocardial acti-vation consistent with LBBB (17,18). Separate analysissuggests that QRSD thresholds for LBBB diagnosis differaccording to sex and that conventional LBBB electrocar-diographic criteria are falsely positive in men morefrequently than in women because of their smaller ventriclesand shorter QRSD than men (10,16). In the current study,we tested the hypothesis that in CRT-D patients, conven-tional diagnosis of LBBB would be associated with betterlong-term survival in women than in men even afteraccounting for baseline comorbidities.

Methods

This study was approved by the U.S. Food and DrugAdministration Research inHuman Subjects Committee andthe Centers forMedicare &Medicaid Services. It included allMedicare patients (107,475 male and 37,167 female subjects)who received CRT-D (International Classification ofDiseases-Ninth Revision-Clinical Modification [ICD-9-CM] procedure code 0051) between July 1, 2002, andDecember 31, 2008, who were also continuously enrolled inMedicare Part A (inpatient hospital coverage) and B(outpatient medical coverage) for�6 months before CRT-Dimplantation.Comorbidities. We compared the prevalence and prog-nostic significance of demographic data and several comor-bidities as documented in Medicare claims files by usingICD-9-CM codes. These variables include age, reason forentrance into Medicare, race, year of device implantation,preexisting comorbidities (previous myocardial infarction,

hypertension, LBBB, right bundle branch block [RBBB],ischemic cardiomyopathy, diabetes mellitus, atrial fibrilla-tion/flutter, previous stroke, previous HF hospitalizations,and end-stage renal disease). To account for risk associatedwith unmeasured comorbidities, we also included theCharlson comorbidity index or “Charlson score” in allmodels (19). The Charlson score is an index used to predict10-year mortality based on whether a patient has certainhealth conditions; the specific conditions are listed in theOnline Appendix. In the Cox proportional hazards models,race was classified as black or non-black. Year of deviceimplantation was defined as the year the procedure code0051 was recorded in the patient’s record. Preexistingcomorbidities were assessed by determining if a beneficiaryhad an ICD-9-CM diagnosis code in the 6 monthsbefore CRT-D implantation; the Online Appendix lists thespecific ICD-9-CM codes.Outcomes. The primary outcome for this study was all-cause mortality. Mortality was determined from the Medi-care Master Beneficiary Summary File from the Centers forMedicare & Medicaid Services, which documents date ofdeath for beneficiaries assessed from the Social SecurityAdministration. Secondary analyses were performed for theendpoint all-cause mortality or in-patient HF hospitaliza-tion as a primary diagnosis (ICD-9-CM code 428.x).Patients were censored if they did not reach the primary (orsecondary) endpoint before December 31, 2009, or if theywere no longer continuously enrolled in Medicare Part B.Statistical analyses. Kaplan-Meier curves stratified for sexand LBBB were generated for total survival for up to72 months of follow-up. The significance of demographicand comorbidity characteristics were assessed in univariateand multivariable Cox proportional hazards models for thetotal population as well as for men and women indepen-dently. The proportional hazards assumption was verified byusing plots of the log (-log) survival cures and by using Coxtest for continuous time interaction. Multivariable modelsincluded age, sex, race, year of device implantation, and allpreexisting comorbidities, including the Charlson score. Theinteractions of sex and each of the comorbidities (includingLBBB) were also evaluated to determine if the prognosticvalue of these comorbidities differed according to sex.

All analyses were conducted by using SAS version 9.2(SAS Institute, Inc., Cary, North Carolina).

Results

Of the 144,642 Medicare CRT-D patients included in thisstudy, 107,475 (74%) were male and 37,167 (26%) werefemale (Table 1). Men (compared with women) were morecommonly white (90% vs. 84%) and more frequently hadischemic cardiomyopathy (69% vs. 53%) and atrial fibrilla-tion/flutter (56% vs. 48%). Women were more frequentlyblack (13% vs. 7%) and more frequently had LBBB (53% vs.39%). Other comorbidities (including Charlson score), age,reason for entering Medicare, region of residence, and year of

Table 1 Baseline Characteristics According to Sex

CharacteristicFemale Subjects(n ¼ 37,167)

Male Subjects(n ¼ 107,475)

Total(N ¼ 144,642)

Comorbidities

Myocardial infarction 5,900 (16) 18,234 (17) 24,134 (17)

Hypertension 32,346 (87) 90,098 (84) 122,444 (85)

LBBB 19,596 (53) 42,328 (39) 61,924 (43)

RBBB 1,710 (5) 8,328 (8) 10,038 (7)

Ischemic cardiomyopathy 19,580 (53) 74,236 (69) 93,816 (65)

Diabetes 17,813 (48) 49,892 (46) 67,705 (47)

Atrial fibrillation/flutter 17,858 (48) 60,715 (56) 78,573 (54)

Stroke 2,840 (8) 8,005 (7) 10,845 (7)

Previous heart failure hospitalization 9,687 (26) 23,405 (22) 33,092 (23)

ESRD 869 (2) 2,917 (3) 3,786 (3)

Charlson score

0 1,432 (4) 4,531 (4) 5,963 (4)

1 10,477 (28) 26,986 (25) 37,463 (26)

2 11,029 (30) 31,644 (29) 42,673 (30)

3 7,270 (20) 21,679 (20) 28,949 (20)

�4 6,959 (19) 22,635 (21) 29,594 (20)

Age (yrs)

<45 343 (<1) 912 (<1) 1,255 (<1)

45–54 1,038 (3) 3,004 (3) 4,042 (3)

55–64 31,83 (9) 9,312 (9) 12,495 (9)

65–74 14,641 (39) 41,098 (38) 55,739 (39)

75–84 15,623 (42) 46,071 (43) 61,694 (43)

>84 2,339 (6) 70,78 (7) 9,417 (7)

Race

White 31,035 (84) 96,348 (90) 127,383 (88)

Black 4,829 (13) 7,711 (7) 12,540 (9)

Asian 206 (<1) 622 (<1) 828 (<1)

Hispanic 661 (2) 1,426 (1) 2,087 (1)

North American Native 192 (<1) 439 (<1) 631 (<1)

Other, non-North American Native 217 (<1) 840 (<1) 1,057 (<1)

Other/unknown 27 (<1) 89 (<1) 116 (<1)

Reason for entrance into Medicare

Aged without ESRD 27,752 (75) 75,996 (71) 10,3748 (72)

Aged with ESRD 36 (<1) 114 (<1) 150 (<1)

Disabled without ESRD 9,165 (25) 30,690 (29) 39,855 (28)

Disabled with ESRD 58 (<1) 196 (<1) 254 (<1)

ESRD only 120 (<1) 429 (<1) 549 (<1)

Unknown 36 (<1) 50 (<1) 86 (<1)

Year of CRT-D implantation

2002 316 (<1) 1,219 (1) 1,535 (1)

2003 3,088 (8) 11,598 (11) 14,686 (10)

2004 5,772 (16) 18,759 (17) 24,531 (17)

2005 7,940 (21) 22,412 (21) 30,352 (21)

2006 7,476 (20) 19,952 (19) 27,428 (19)

2007 6,758 (18) 17,941 (17) 24,699 (17)

2008 5,817 (16) 15,594 (15) 21,411 (15)

Values are n (%).CRT-D ¼ cardiac resynchronization therapy defibrillator; ESRD ¼ end-stage renal disease; LBBB ¼ left bundle branch block; RBBB ¼ right bundle

branch block.

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CRT-D implantation were similar across sexes. Follow-updata were available for a median of 28 months (interquartilerange: 15 to 46 months) with 5,852 patients remaining at 72months and up to 90 months of follow-up for some patients.

After 72 months of follow-up, 57,043 patients (60% ofthe uncensored population) had died. Women had

significantly lower mortality than men (54% vs. 62%)(Fig. 1A), and the separation of these survival curvescontinued to diverge over the length of follow-up. Patientswith LBBB also had lower mortality than those withoutLBBB (56% vs. 63%) (Fig. 1B). When stratifying accordingto both sex and LBBB status (Fig. 1C), women with LBBB

Figure 1 Kaplan-Meier Plots of Survival

Results are stratified according to (A) sex, (B) left bundle branch block (LBBB), or

(C) both. Women had better survival than men, and LBBB patients had better

survival than non-LBBB patients. CRT-D ¼ cardiac resynchronization therapy

defibrillators.

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had the lowest mortality (49%), whereas men without LBBBhad the highest mortality (64%). Non-LBBB women andLBBB men had intermediate mortalities (59% and 60%,respectively).

Univariate and multivariable models for death. Coxproportional hazards for overall mortality were determinedfor the total population and for men and women indepen-dently. Figure 2 contains forest plots of adjusted hazard ratios(HRs); Online Tables 1 and 2 contain univariateand multivariable HRs. In the overall population, allcomorbidities (including ischemic cardiomyopathy and atrialfibrillation/flutter) were associated with higher rates of death,with the exception of LBBB, which was associated with an18% lower rate of death (adjusted HR: 0.82 [95% confidenceinterval (CI): 0.81 to 0.84]). Presence of end-stage renaldisease had the strongest associated mortality rate (adjustedHR: 2.55 [95% CI: 2.46 to 2.67]). Male sex was associatedwith higher mortality (adjusted HR: 1.19 [95% CI: 1.17 to1.22]), as was black race (adjusted HR: 1.18 [95% CI: 1.14 to1.21]). With the exception of hypertension, similar trendswere seen in univariate and multivariable models. Hyper-tension was associated with a higher rate of death inunivariate analysis (HR: 1.14 [95% CI: 1.12 to 1.17]) buta lower rate of death in the multivariable analysis (adjustedHR: 0.94 [95% CI: 0.91 to 0.96]).

When male and female patients were analyzed separately(Figs. 2B and 2C, Online Table 2), all comorbidities exceptLBBB (and hypertension in multivariable analyses) main-tained their association with higher rates of mortality. In theunivariate analysis, LBBB was associated with a 31% lowermortality rate in women (HR: 0.69 [95% CI: 0.67 to 0.71])but only a 16% lower mortality rate in men (HR: 0.84 [95%CI: 0.82 to 0.85]). Controlling for comorbidities, LBBB wasstill associated with a 26% lower mortality rate in women(adjusted HR: 0.74 [95% CI: 0.71 to 0.77]) compared witha 15% lower mortality rate in men (adjusted HR: 0.85 [95%CI: 0.83 to 0.87]) (Fig. 2D). Evaluating the interaction ofsex and LBBB demonstrated that after accounting for othercomorbidities, the presence of LBBB was associated witha lower mortality in women than in men (p < 0.0001). (Allinteraction p values are listed in Online Table 3). Incontrast, ischemic cardiomyopathy and atrial fibrillation/flutter were associated with lower rates of death in mencompared with women (adjusted HRs: 1.02 vs. 1.10 and1.25 vs. 1.34, respectively).Univariate and multivariable models for HF hospitali-zation or death. Similar patterns were seen in all modelsfor the combined outcome of HF hospitalization or death(Figs. 3 and 4, Online Tables 4 and 5). All comorbiditieswere associated with increased rates of HF hospitalization ordeath with the exception of LBBB, which was associatedwith an 18% lower rate of event (adjusted HR: 0.82 [95%CI: 0.81 to 0.83]) (Fig. 4A). As with mortality alone, thereduced rate of HF hospitalization or death associated withLBBB was more substantial in women (31% lower eventrate) compared with men (16% lower event rate) (OnlineTable 5). This difference in the prognostic significance ofconventional LBBB diagnosis according to sex remainedsignificant after controlling for baseline characteristics (26%lower event rate in women compared with 15% in men)

Figure 2 Forest Plots of Multivariable HRs for Death

Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) for (A) the total population, (B) female patients, and (C) male patients. D demonstrates the HRs and 95%

CIs for LBBB for both the female and male population independently. The CIs for these 2 estimates do not overlap. HF ¼ heart failure; RBBB ¼ right bundle branch block; other

abbreviations as in Figure 1.

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(Fig. 4, Online Table 5). Gender interaction p values for HFhospitalization or death are listed in Online Table 6.

Discussion

The diagnosis of LBBB is associated with significantlygreater survival in women than in men receiving CRT-D,and this discrepancy is not explained by differences incomorbidities. Men more frequently had ischemic cardio-myopathy and atrial fibrillation/flutter, which have beenassociated with worse CRT-D outcomes (20,21). Althoughdifferences in baseline risk profiles may contribute to thedifferences in CRT-D outcomes according to sex, multi-variable analysis demonstrated that after accounting forbaseline comorbidities, a large difference in the association

of LBBB with death remained (15% lower mortality inmales vs. 26% in females). Furthermore, a significantinteraction between sex and LBBB confirmed that theLBBB diagnosis in and of itself carries a different prognosisfor female and male CRT-D recipients. These findingssuggest that the sex difference in LBBB mortality rates isindependent of differences in baseline risk profiles.LBBB and CRT. When the left bundle branch is blocked,the LV lateral wall is activated significantly later than theseptum, which creates dyssynchronous contraction; dyssyn-chrony can be minimized by CRT to improve cardiac output.Other conditions that prolong QRSD (e.g., RBBB, LVhypertrophy, intramural conduction delay) maintain coordi-nated LV activation by the rapidly conducting LV Purkinjesystem. Previous work has suggested that the reduction in

Figure 3Kaplan-Meier Plots of Survival and FreedomFrom HF Hospitalization

Results are stratified according to (A) sex, (B) LBBB, or (C) both. Similar to

analysis with death alone, women and LBBB patients had better survival free of

heart failure (HF) hospitalization or death compared with men and non-LBBB

patients, respectively. Abbreviations as in Figure 1.

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mortality and HF hospitalizations associated with CRT maybe limited to patients with LBBB (6,7,22). Retrospectiveanalysis of the MADIT-CRT (Multicenter Automatic

Defibrillator Implantation Trial–Cardiac ResynchronizationTherapy) study found that LBBB patients receiving CRT-Dhad a 53% reduction in death or HF events, whereas patientswith RBBB or nonspecific LV conduction delay receivingCRT-D had a 24% increase in HF events or death (althoughthese results were not statistically significant) (6). Further-more, the outcome was even worse in patients with nonspe-cific LV conduction delay than RBBB. Newly developed,stricter diagnostic criteria for LBBB suggest that manypatients who receive a diagnosis for LBBB according toconventional electrocardiographic criteria (defined in thisstudy by using the ICD-9-CM code) and do not meet thestrict LBBB criteria may belong to the nonspecific LVconduction delay group (10). One study comparing CRToutcomes between patients who met strict LBBB criteriaversus those who only met conventional LBBB criteria foundthat those meeting the strict criteria had better echocardio-graphic response and higher event-free survival, which wasindependent of QRSD (23).

Although it is possible that LBBB truly has differentprognostic significance according to sex, recent studies havesuggested that current diagnostic criteria for LBBB misdi-agnose up to one-third of patients and that this misclassifi-cation occurs more frequently in men than in women(10,17,18,24). Women have shorter normal QRSD thanmen (87.1 � 8.7 ms vs. 92.7 � 9.3 ms, respectively) (16) innormal conduction; thus, recommendations for sex-specificLBBB criteria use a QRSD threshold of 130 ms for womenand 140 ms for men (10,24). These thresholds suggest thatmany patients diagnosed with LBBB by using conventionalcriteria may have false-positive findings and that the potentialmisclassified population is larger in men than in women (allmale patients withQRSD120 to 140ms vs. 120 to 130ms forwomen). Therefore, it is possible that LBBB predicts betteroutcomes in women because among those diagnosed withLBBB, women more frequently exhibit truly dyssynchronousactivation of the left ventricle and are thus more likely tobenefit from resynchronization therapy.Sex differences in HF and CRT. In both LBBB and non-LBBB patients, women in the current study had a lower rateof mortality than men throughout follow-up. This finding isconsistent with previous studies in both the United Statesand Europe, which demonstrated that women have betterlong-term survival after CRT than men (25–27). Althoughthe source of this disparity cannot be determined from ourstudy, it is possible that sex differences in true LBBBprevalence is a major factor driving the outcome disparity inmen and women with LBBB. For non-LBBB patients,other studies have demonstrated that women also morefrequently have nonischemic cardiomyopathies and smallermyocardial scar sizes than men, both of which are associatedwith better outcomes after CRT (12,13,25–28).Study limitations. The current study relied on assessingbaseline characteristics and outcomes as documented byMedicare billing data and ICD-9-CM codes. It is possiblethat coding or entry errors may have resulted in misdiagnosis

Figure 4 Forest Plots of Multivariable HRs for HF Hospitalization or Death

Multivariable HRs with 95% CIs for (A) the total population, (B) female patients, and (C) male patients. D demonstrates the HRs and 95% CIs for LBBB for both the female

and male population independently. The CIs for these 2 estimates do not overlap. Abbreviations as in Figures 1, 2, and 3.

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of baseline characteristics, including LBBB, previous HFhospitalization, and CRT-D implantation. In addition,some diagnostic codes are broad (e.g., 427.3x refers to atrialfibrillation or atrial flutter) and may result in overestimationor underestimation of some comorbidities. However, thispossibility is equally likely in men and women, and the largesample size makes these results more robust and less proneto errors due to miscoding. In addition, previous work hasdemonstrated that adjudicating Medicare claims resulted inchanges in <3% of claims, suggesting that the data entryerrors are minimal (29). The sex differences demonstratedin this study may be the result of indirect effects from un-measured variables. All models were designed to be robustand include all available comorbidities likely related to theoutcomes. In addition, the study would be strengthened byincluding analysis with QRSD, New York Heart

Association class, and LV ejection fraction; however, thesevariables are not available in Medicare billing records.

Conclusions

The results of this study demonstrated that among Medicarebeneficiaries undergoing implantation with CRT-D, LBBBpredicts better outcomes among women than men. Onepossible explanation for this sex disparity is that men mayhave more false-positive LBBB diagnoses than women. Toour knowledge, this is the first time that LBBB has beenshown to portend significantly better long-term survivalbenefit in women than men receiving CRT-D. Developingmore patient-specific selection criteria for CRT-D mayreduce the risks and costs associated with inappropriatetherapy. Future studies should investigate appropriate

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QRSD thresholds in men and women that best identifyCRT-D candidates.

Reprint requests and correspondence: Dr. David G. Strauss,FDA, Center for Devices and Radiological Health, 10903 NewHampshire Avenue, WO 62-1126, Silver Spring, Maryland 20993.E-mail: david.strauss@fda.hhs.gov.

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Key Words: cardiac resynchronization therapy - left bundle branchblock - sex.

APPENDIX

For an expanded Methods section and supplemental tables, please see theonline version of this paper.